Each of the herein cited patent applications, and all documents cited in the text or during the prosecution of the herein cited patent applications (xe2x80x9capplication cited documentsxe2x80x9d)xe2x80x94either cited by the Examiner (e.g., Patent Office, such as the U.S. or French Patent Office or WIPO or Searching Authority) or by the applicant(s)xe2x80x94as well as all documents cited or referenced in application cited documents, are hereby incorporated herein by reference. Further, all documents cited herein (xe2x80x9cherein cited documentsxe2x80x9d) and all documents cited or referenced in herein cited documents are hereby incorporated herein by reference.
Further, the following documents are hereby incorporated herein by reference:
U.S. Pat. No. 5,885,607, issued to Jeannin on Mar. 23, 1999;
U.S. Pat. No. 5,801,189, issued to Twinn on Sep. 1, 1998;
U.S. Pat. No. 5,232,940, issued to Hatton on Aug. 3, 1993;
U.S. Pat. No. 5,122,530, issued to Tomioka on Jun. 16, 1992;
U.S. Pat. No. 5,567,429, issued to Senbo on Oct. 22, 1996;
U.S. Pat. No. 4,963,575, issued to Buntain on Oct. 16, 1990;
U.S. Pat. No. 5.516,787, issued to Takada on May 14, 1996;
U.S. Pat. No. 5,629,334, issued to Takada on May 13, 1997;
EP 0 295 117 with an international filing date of Jun. 10, 1988;
PCT/EP98/01224 with an international filing date of Mar. 1, 1998;
PCT/EP97/06503 with an international filing date of Nov. 21, 1997;
Bloomquist, J. R., Ion Channels as Targets for Insecticides, Annu. Rev. Entomol.; Vol. 41,163-90 (1996);
Hainzl, D. et al, Mechanisms for Selective Toxicity of Fipronil Insecticide and Its Sulfone Metabolite and Desulfinyl Photoproduct, Chem. Res. Toxicol; Vol. 11(12), 1529-35 (1998);
Hainzi, D. et al, Fipronil Insecticide: Novel Photochemical Desulfinylation with Retention of Neurotoxicity, Proc. Natl. Acad. Sci. USA; Nov. 12;93(23), 12764-7 (1996); and Cochet, P. et al, Skin Distribution of Fipronil by Microautoradiography following Topical Administration to the Beagle Dog, Eur. J. Drug Metab. Pharmacokinet. Jul-Sep; 22(3): 211-6 (1997).
This invention envisions compounds, compositions, formulations and methods of use involving a phenylpyrazole as depicted herein or in herein cited documents; and phenylpyrazoles depicted herein or in herein cited documents can be used in the compositions, formulations and methods of herein cited patent applications. Further, the invention envisions compounds that degrade, e.g., biodegrade or photodegrade or chemically degrade, to phenylpyrazoles as depicted herein or in herein cited documents or to same or similar derivatives of phenylpyrazoles herein depicted from degradation (e.g., biodegradation, photodegradation, chemical, degradation); for instance, if a herein depicted phenylpyrazole degrades to compound xe2x80x9cXxe2x80x9d, the invention envisions compounds xe2x80x9cXxe2x80x9d and other phenylpyrazoles that degrade to compound xe2x80x9cXxe2x80x9d. The invention also envisions compositions, formulations, and methods of use involving compounds that degrade to phenylpyrazoles as depicted herein or in herein cited documents or to same or similar derivatives of phenylpyrazoles herein depicted from degradation; for example, pour-on formulations, spot-on formulations, formulations and/or methods for distribution in sebacious glands, formulations and/or methods of preventing, treating, controlling, and/or combating myasis, and the like, as well as in compositions, formulations, and uses of herein cited patent applications. (A compound that degrades to a phenylpyrazole herein depicted or that degrades to a same or similar derivative of a phenylpyrazole herein depicted from degradation, e.g., a phenylpyrazole that degrades to compound xe2x80x9cXxe2x80x9d that is a degradation derivative of a herein depicted phenylpyrazole is herein termed a xe2x80x9cpro-pp-compoundxe2x80x9d.) More in particular, herein depicted phenylpyrazoles as well as those of documents cited herein, e.g. PCT/EP97/06503 or WO 98/24769, which is equivalent to U.S. Pat. No. 6,265,430, degrade to the active compound fipronil sulfide (sulfide on the 4 position) and thus, the invention comprehends the use of phenylpyrazoles depicted herein and in documents cited herein that degrade to fipronil sulfide, in for example, pour-on formulations, spot-on formulations, formulations and/or methods for distribution in sebacious glands, formulations and/or methods of preventing, treating, controlling, and/or combating myasis, and the like, as well as in compositions, formulations, and uses of herein cited patent applications. Ethaprol (or a 4-elhylsulfoxide derivative of herein depicted phenylpyrazole) as well as compounds of the herein formula wherein there is a sulfideat the 4 position and/or R1 xe2x95x90CN, SO and/or R3xe2x95x90CF3 or alkyl (e.g., 4-haloalkyl sulfoxide sulfones, 3-cyanos, 3-cyano-pro-pp-compounds) are useful, e.g., in pour-on formulations and methods. Formulations, compositions and methods of use can include an additional active ingredient, such as a macrolide antibiotic and/or an insect growth regulator (IGR), or the like, which can be admixed with or administered separately from, e.g., sequentially, with the phenylpyrazole and/or pro-pp-compound (or the macrolide antibiotic and/or IGR can itself, without the phenylpyrazole and/or pro-pp-compound, be the active ingredient in the formulation, such as pour-on or spot-on formulation or a formulation for distribution in the sebacious glands, as disclosed herein arm herein cited patent applications). These and other embodiments are provided in this text.
The present invention relates to a direct pour-on skin solution which contains an antiparasitic product and is intended to be applied topically to cattle and sheep.
The invention also relates to the use of antiparasitic compounds for the preparation of this skin solution, as well as to a treatment process relating thereto.
Cattle and sheep are affected by a large number of parasites.
The main ones are ticks of the genus Boophilus, among which mention may be made of the species microplus (cattle tick), decoloratus and anulatus. 
The other main parasites of cattle and sheep are indicated in order of decreasing importance:
myiases such as Dermatobia hominis (known as Berne in Brazil) and Cochlyomia hominivorax (greenbottle); sheep myiases such as Lucilia sericata, Lucilia cuprina (known as blowfly strike in Australia, New Zealand and South Africa). These are flies whose larva constitutes the animal parasite.
flies proper, namely those whose adult constitutes the parasite, such as Haematobia irritans (horn fly).
lice such as Linognathus vitulorum, etc.
galls such as Sarcoptes scabiei and Psoroptes ovis. 
Ticks, in particular Boophilus microplus, are very closely attached to the pasture in which they live and are particularly difficult to control.
There is at the present time no truly effective method for controlling ticks, and less still an effective way of controlling the set of parasites indicated above.
WO-A-87/3781, EP-A-295,117 and EP-A-500,209 describe a class of insecticides which are N-phenyl-pyrazole derivatives. These compounds are given as having activity against a very large number of parasites, including Boophilus microplus, in fields as varied as agriculture, public health and veterinary medicine. The general teaching of these documents indicates that these insecticidal compounds may be administered via different routes; oral, parenteral, percutaneous and topical routes. Topical administration comprises, in particular, oral formulations, baits, dietary supplements, skin solutions (pour-on), solutions for spraying (sprays), baths, showers, jets, powders, greases, shampoos, creams, etc. The pour-on type skin solutions are designed for percutaneous administration. Example 9 of EP-A-295,117 and Example 29I of EP-A-500,209 describe a pour-on type skin solution containing 15% insecticide and 85% dimethyl sulphoxide, for percutaneous administration of the insecticide.
EP-A-296,381 also describes pyrazole compounds having insecticidal activity in the field of agriculture, public health and veterinary medicine. Boophilus microplus is one of the very many targets mentioned. There are very many forms of administration here also, and these include, for example, solutions, emulsions, suspensions, powders, pastes, granules and aerosols.
The problem which is posed is to find an effective means which is entirely suitable for controlling the, parasites of cattle and sheep, in particular ticks, most particularly Boophilus microplus in cattle and in particular lice and blowfly in sheep, under the conditions in which these animals are reared
The Applicant has found that it is possible to effectively control Boophilus microplus for cattle using a specific topical formulation. The Applicant has also found that this formulation is effective against sheep lice and sheep flies known as xe2x80x9cblowflyxe2x80x9d.
The aim of the present invention is thus to provide a novel composition which is entirely effective against Boophilus microplus and also against all of the other parasites described above such as, in particular, sheep lice and xe2x80x9cblowflyxe2x80x9d, this composition being entirely suitable for controlling these parasites under the conditions in which these animals are reared.
Another aim of the invention is to provide such a formulation which has a long period of efficacy, preferably longer than or equal to two months.
Another aim of the invention is to provide such a formulation which is quick and easy to use and entirely compatible with use on herds or flocks containing a large number of animals.
Another aim of the invention is to provide such a formulation which is particularly suitable for extensive pasture rearing and for use intended to protect animals during the period of rounding up and finishing (Feed Lot in USA), namely the final period of rearing in which a large number of animals are herded into a small enclosure over an average period of two months preceding slaughter.
The subject of the present invention is thus a direct pour-on skin solution, intended to eliminate parasites from cattle and sheep, most particularly ticks, especially Boophilus microplus in cattle and lice and blowfly in sheep, comprising from 0.05 to 25% weight/volume, relative to the total solution, of a compound of formula (I) 
in which:
R1 is CN or methyl or a halogen atom;
R2 is S(O)nR3 or 4,5-dicyanoimidazol-2-yl or haloalkyl;
R3 is alkyl or haloalkyl;
R4 represents a hydrogen or halogen atom; or a radical NR5R5R6, S(O)mR7, C(O)R7, C(O)Oxe2x80x94R7, alkyl, haloalkyl or OR8, or a radical xe2x80x94Nxe2x95x90C (R9) (R10);
R5 and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)rCF3 radical; or R5 and R6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur;
R7 represents an alkyl or haloalkyl radical;
R8 represents an alkyl or haloalkyl radical or a hydrogen atom;
R9 represents an alkyl radical or a hydrogen atom;
R10 represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, xe2x80x94O-alkyl, xe2x80x94S-alkyl, cyano or alkyl;
R11 and R12 represent, independently of each other, a hydrogen or halogen atom, or optionally CN or NO2;
R13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF5 group;
m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a radical Cxe2x80x94R12, the other three valency positions of the carbon atom forming part of the aromatic ring;
with the proviso that, when R1 is methyl, either R3 is haloalkyl, R4 is NH2, R11 is Cl, R13 is CF3 and X is N; or R2 is 4,5-dicyanoimidazol-2-yl, R4 is Cl, R11 is Cl, R13 is CF3 and X is xe2x95x90Cxe2x80x94Cl;
in a formulation at low volume, designed to release the compound (I) onto the skin and the hairs for a contact action against parasites.
Preferably, in formula (I), R1 is CN or methyl;
R2 is S(O)nR3;
R3 is alkyl or haloalkyl;
R4 represents a hydrogen or halogen atom; or a radical NR5R6, S(O)mR7, C(O)R7, alkyl, haloalkyl or OR8 or a radical xe2x80x94Nxe2x95x90C (R9) (R10);
R5 and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl or S(O)rCF3 radical; or R5 and R6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms, such as oxygen or sulphur;
R7 represents an alkyl or haloalkyl radical;
R8 represents an alkyl or haloalkyl radical or a hydrogen atom;
R9 represents an alkyl radical or a hydrogen atom;
R10 represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, xe2x80x94O-alkyl, xe2x80x94S-alkyl, cyano or alkyl;
R1l and R12 represent, independently of each other, a hydrogen or halogen atom;
R13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF5 group;
m, n, q, and r represent, independently of each other, an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a radical Cxe2x80x94R12, the other three valency positions of the carbon atom forming part of the aromatic ring;
with the proviso that, when R1 is methyl, then R3 is haloalkyl, R4 is NH2, R11 is Cl, R13 is CF3 and X is N.
However, low concentrations of from 0.05 to 10% weight/volume, more particularly from 0.1 to 2%, are preferred. Optimally, the value is between 0.25 and 1.5%, in particular in the region of 1%.
The expression pour-on skin solution is understood to refer to a ready-to-use solution intended to be applied topically and locally on the animal, Preferably on the animal""s back and at several points or along the line of the back, and applied in low volume, preferably of 5 to 20 ml per 100 kg, preferably about 10 ml per 100 kg, with a total volume of from 10 to 150 ml per animal, preferably limited to 50 ml.
The compound acts by simple contact, the parasite becoming impregnated with the compound on contact with the hairs and the skin.
This thereby affords, in a noteworthy manner, a both perfect compatibility with the restrictions of use in extensive grazing, in terms of ease of use in particular, and a spectrum of activity and of efficacy, as well as a period of efficacy, which are suited to this type of rearing.
By working on the concentration of compound (I), in particular of compound A, solutions having note-worthy activities are obtained with, in particular, two months of efficacy against Boophilus microplus, this result never before having been achieved. Moreover, the solution according to the invention allows Boophilus microplus to be totally eliminated from an infested animal in less than 2 days.
As has been stated above, the solution according to the present invention is applied topically, in low volume, to the animal""s back. The compound of formula (I) then diffuses out in a noteworthy manner, this being reflected by a distribution of the compound over the animal""s entire body. It has also been observed that the animals remained protected in the case of passage through water or exposure to rain.
The dose of compound of formula (I) is preferably between 0.1 and 2 mg/kg (animal weight), preferably between 0.25 and 1.5 mg/kg, and in particular about 1 mg/kg.
The compounds of formula (I) in which R1 is CN will be selected most particularly. The compounds in which R2 is S(O)nR3, preferably with n=1, R3 preferably being CF3 or alkyl, for example methyl or ethyl, or alternatively n=0, R3 preferably being CF3, as well as those in which X=C-R12, R12 being a halogen atom, will also be selected. The compounds in which R11 is a halogen atom and those in which R13 is haloalkyl, preferably CF3, are also preferred. In the context of the present invention, compounds combining two or more of these characteristics will advantageously be selected.
A preferred class of compounds of formula (I) consists of compounds such that R1 is CN, R3 is haloalkyl, preferably CF3, or ethyl, R4 is NH2, R11 and R12 are, independently of each other, a halogen atom, and/or R13 is haloalkyl.
In the present invention, the alkyl radicals may contain generally from 1 to 6 carbon atoms. The cycle formed between the divalent alkylene radical representing R5 and R6, as well as with the nitrogen atom to which R5 and R6 are attached, may be generally a cycle of 5, 6 or 7 links.
A most particularly preferred compound of the formula (I) in the invention is 1-[2,6-Cl2 4-CF3phenyl]3-CN 4-[SO-CF3]5-NH2pyrazole, referred to hereinbelow as compound A. This compound A will be used in particular in a proportion of from 0.1 to 2% by weight, more particularly about 1%, relative to the total solution.
Mention may also be made of the two compounds which differ from the above by the following characteristics:
1-n=0, R3=CF3 
2-n=1, R3=ethyl.
The compounds of formula (I) may be prepared according to one or other of the processes described in patent applications WO-A-87/3781, 93/6089, 94/21606 or European patent application EP-A-0,295,117, or any other process which falls within the competence of a specialist skilled in the art of chemical synthesis. For the chemical preparation of the products of the invention, a person skilled in the art is considered as having at his or her disposal, inter alia, all the contents of xe2x80x9cChemical Abstractsxe2x80x9d and the documents cited therein.
It is not departing from the scope of the present invention to incorporate other insecticides into the solution according to the present invention.
The solutions according to the invention, which are advantageously oily, generally comprise a diluent or vehicle and also a solvent (organic solvent) for the compound of formula (I) if the latter is not soluble in the diluent.
As organic solvent which can be used in the invention, mention may be made in particular of: acetyltributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, in particular N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or a mixture of at least two of these solvents.
As vehicle or diluent, mention may be made in particular of:
plant oils such as soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils such as petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium-chain (C8 to C12 in particular) triglycerides.
An emollient and/or spreading and/or film-forming agent will preferably be added, this agent being selected in particular from:
polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils, in particular polydimethylsiloxane (PDMS) oils, for example those containing silanol functionalities, or a 45V2 oil,
anionic surfactants such as alkaline stearates, in particular sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulphates, in particular sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids, in particular those derived from coconut oil,
cationic surfactants such as water-soluble quaternary ammonium salts of formula N+Rxe2x80x2Rxe2x80x3Rxe2x80x2xe2x80x3Rxe2x80x3xe2x80x3, Yxe2x88x92 in which the radicals R are optionally hydroxylated hydrocarbon radicals and Yxe2x88x92 is an anion of a strong acid such as the halide, sulphate and sulphonate anions; cetyltrimethylammonium bromide is among the cationic surfactants which can be used,
amine salts of formula N+Rxe2x80x2Rxe2x80x3Rxe2x80x2xe2x80x3 in which the radicals R are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the cationic surfactants which can be used,
nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated, in particular polysorbate 80, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide,
amphoteric surfactants such as the substituted lauryl compounds of betaine;
or a mixture of at least two of these agents.
The solvent will be used in proportion with the concentration of the compound I and its solubility in this solvent.
For example, compound A has a solubility of 4.3% m/V in acetyl tributyl citrate. It will be sought to have the lowest possible volume.
The vehicle makes up the difference to 100%.
The emollient is preferably used in a proportion of from 0.1 to 10%, in particular from 0.25 to 5%, by volume.
The subject of the present invention is also a process for the elimination of parasites, in particular Boophilus microplus, from cattle and sheep using a direct pour-on skin solution according to the present invention, so as obtain long-lasting and broad-spectrum efficacy, the solution being applied to the animal""s back, preferably along the line of the back at one or more points.
According to a first embodiment, the process consists in applying the solution to the animals in pasture and/or before they arrive in pasture, the application preferably being repeated every month, preferably every two months.
According to a second embodiment, the process consists in applying the solution to the animals before they arrive in the xe2x80x9cfeed Lotxe2x80x9d, it being possible for this application to be the final one before the animals are slaughtered.
Obviously, the process may also consist in combining these two embodiments, namely the first followed by the second.
In all cases, the efficacy advantageously makes it possible to stop any application 1 to 3 months before slaughter, in particular between 1.5 and 2.5 months, more particularly about two months before slaughter.
The solutions according to the invention may be applied using any means known per se, preferably using an applicator gun or a metering flask.
The aim of the method is not therapeutic and is, in particular, to cleanse the skin and the hairs of the animals by eliminating the parasites which are present thereon, as well as their residues and dejections. The result of this is that the animals are no longer stressed by the parasites and their bites, this having positive consequences, for example on their growth and on the use of their food ration.
Another subject of the invention is a therapeutic method using the external device according to the invention, intended for the treatment and prevention of parasitoses having pathogenic consequences.
The subject of the present invention is also the use of the compounds I, in particular compound A, for the manufacture of a direct pour-on skin solution comprising the compound (I) in a low volume and designed to release the compound (I) onto the skin and the hairs for a contact action against the parasites of cattle and sheep, in particular cattle ticks, such as Boophilus microplus, and sheep blowfly and lice.
The use according to the invention is directed towards producing skin solutions as described above.
The present invention will now be described in greater detail with the aid of non-limiting embodiment examples which demonstrate the activity of the solutions according to the present invention, with reference to the attached drawings in which:
FIG. 1 is a graph showing the efficacy, against Boophilus microplus, of skin solutions according to the invention, with a 0.25%, 0.5% and 1% content, relative to a control, this graph including, on the x-axis, the time in days after application of the skin solutions, and, on the y-axis to the left, the number of ticks counted on the animals on which the skin solutions according to the invention are applied, and, on the y-axis to the right, the number of ticks counted in the controls;
FIG. 2 is a graph showing the population of ticks in animals which have received the placebo according to Example 2, with, on the x-axis, the time in days, and, on the y-axis, the number of ticks; and
FIG. 3 compares the efficacy of a skin solution according to the invention containing 1% compound A (solid circles) with a skin solution containing 1% flumethrin (rings), with, on the x-axis, the time in days, and, on the y-axis, the number of ticks.